The Journal of Experimental Medicine
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Published online May 12, 2008
doi:10.1084/jem.20080277
The Journal of Experimental Medicine, Vol. 205, No. 6, 1395-1408
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Thompson et al.
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ARTICLE

 Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7

Benjamin J. Thompson1,2,3, Vladimir Jankovic4, Jie Gao1,2, Silvia Buonamici1,2, Alan Vest1,2, Jennifer May Lee4, Jiri Zavadil1,2, Stephen D. Nimer4, and Iannis Aifantis1,2

1 Department of Pathology and 2 NYU Cancer Institute, New York University School of Medicine, New York, NY 10016
3 Medical Scientist Training Program, University of Chicago, Chicago, IL 60637
4 Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

CORRESPONDENCE Iannis Aifantis: iannis.aifantis{at}med.nyu.edu

Ubiquitination is a posttranslational mechanism that controls diverse cellular processes. We focus here on the ubiquitin ligase Fbw7, a recently identified hematopoietic tumor suppressor that can target for degradation several important oncogenes, including Notch1, c-Myc, and cyclin E. We have generated conditional Fbw7 knockout animals and inactivated the gene in hematopoietic stem cells (HSCs), progenitors, and their differentiated progeny. Deletion of Fbw7 specifically and rapidly affects hematopoiesis in a cell-autonomous manner. Fbw7–/– HSCs show defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, Fbw7–/– progenitors are unable to colonize the thymus, leading to a profound depletion of T cell progenitors. Deletion of Fbw7 in bone marrow (BM) stem cells and progenitors leads to the stabilization of c-Myc, a transcription factor previously implicated in HSC self-renewal. On the other hand, neither Notch1 nor cyclin E is visibly stabilized in the BM of Fbw7-deficient mice. Gene expression studies of Fbw7–/– HSCs and hematopoietic progenitors indicate that Fbw7 regulates, through the regulation of HSC cycle entry, the transcriptional "signature" that is associated with the quiescent, self-renewing HSC phenotype.

Abbreviations used: DN, double negative; ES, embryonic stem; ETP, early T cell progenitor; HSC, hematopoietic stem cell; LSK, lineage–Sca-1+c-Kit+; LT-HSC; long-term HSC; MP, myeloid progenitor; SCF, Skp1/Cul1/F-box protein; T-ALL, T cell–acute lymphoblastic leukemia.


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